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Purpose: MIXTURE is a simultaneous morphological and quantitative imaging sequence developed by Philips that provides high-resolution T2 maps from the imaged series. We aimed to compare the T2 maps of MIXTURE and SHINKEI-Quant (S-Q) in the cervical spine and to examine their usefulness in the functional diagnosis of cervical radiculopathy., Methods: Seven healthy male volunteers (mean age: 31 ± 8.0 years) and one patient with cervical disc herniation (44 years old, male) underwent cervical spine magnetic resonance imaging (MRI), and T2-mapping of each was performed simultaneously using MIXTURE and S-Q in consecutive sequences in one imaging session. The standard deviation (SD) of the T2 relaxation times and T2 relaxation times of the bilateral C6 and C7 dorsal root ganglia (DRG) and C5/6 level cervical cord on the same slice in the 3D T2-map of the cervical spine coronal section were measured and compared between MIXTURE and S-Q., Results: T2 relaxation times were significantly shorter in MIXTURE than in S-Q for all C6, C7 DRG, and C5/6 spinal cord measurements. The SD values of the T2 relaxation times were significantly lower for MIXTURE in the C5/6 spinal cord and C7 DRG. In cervical disc herniation, MRI showed multiple intervertebral compression lesions with spinal canal stenosis at C5/6 and disc herniation at C6/7., Conclusion: MIXTURE is useful for preoperative functional diagnosis. T2-mapping using MIXTURE can quantify cervical nerve roots more accurately than the S-Q method and is expected to be clinically applicable to cervical radiculopathy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

To guide the treatment of malignant neuropathic pain (MNP) in clinical practice, by inoculating MADB-106 breast cancer cells into the right L4 nerve root in Sprague-Dawley rats, a rat model of MNP was established, providing basic conditions for the study of neuropathic pain and development and application of therapeutic drugs. As the tumor grew over time, it pressed the nerve roots, causing nerve damage. The spinal nerve ligation (SNL) model, which is a neuropathic pain model widely used in rats, was compared with the L4 nerve root SNL model, and histologic examination of the nerve tissue of both models was performed by electron microscopy. In addition to the infiltration and erosion of the L4 nerve by tumor cells, the tumor tissue gradually grew and compressed the L4 nerve roots, resulting in hyperalgesia of the rat's posterior foot on the operative side. Some spontaneous pain phenomena were also observed, such as constant lifting or licking of the posterior foot on the operative side under quiet conditions. Electron microscopy images showed that nerve injury was due to progressive compression by the tumor, cells of which were visualized, but the injury was lighter than that in SNL rats. Imaging showed a paravertebral tumor near the L4 nerve root in the carcinomatous neuropathic pain model rat. These results suggest that progressive compression of the nerve by a malignant tumor leads to nerve damage similar to the behavioral changes associated with chronic compression injury resulting from a loose ligature of the nerve. The cancer neuropathologic pain model at the L4 nerve root was successfully established in Sprague-Dawley rats., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and all the authors listed have approved the manuscript that is enclosed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To test whether multiple-level unilateral thoracic spinal nerves (TSN) resection can induce the initial thoracic cage deformity to cause early onset thoracic scoliosis in an immature porcine model; and 2) to create an early onset thoracic scoliosis in a large animal model that can be used to evaluate growth-friendly surgical techniques and instruments in growing spine researches., Methods: Seventeen one-month-old pigs were assigned to 3 groups. In group 1 (n = 6), right TSN were resected from T7 to T14 with the contralateral (left) paraspinal muscle exposing and stripping. In group 2 (n = 5), the animals were treated in the same way except the contralateral (left) side was intact. In group 3 (n = 6), bilateral TSN were resected from T7 to T14. All animals were followed up for 17-weeks. Radiographs were measured and analyzed the correlation between the Cobb angle and thoracic cage deformity. A histological examination of the intercostal muscle (ICM) was performed., Results: In the groups 1 and 2, an average 62 ± 12° and 42 ± 15° right thoracic scoliosis with apical hypokyphosis of a mean - 5.2 ± 16° and - 1.8 ± 9° were created, respectively, during 17-weeks follow up. All curves were located at the operated levels with the convexity toward the TSN resection side. Statistical analysis demonstrated that the thoracic deformities were strongly correlated with the Cobb angle. In group 3, no scoliosis was created in any animal, but an average thoracic lordosis of - 32.3 ± 20.3° was seen. The histological examination showed the ICM denervation on the TSN resection side., Conclusion: Unilateral TSN resection induced the initial thoracic deformity toward the TSN resection side resulting in thoracic hypokyphotic scoliosis in an immature pig model. This early onset thoracic scoliosis model could be used to evaluate the growth-friendly surgical techniques and instruments in future growing spine researches., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Previous studies reported that spinal nerve edema on magnetic resonance myelography (MRM) and leg pain at rest were specifically observed in symptomatic lumbar foraminal stenosis patients. However, the correlation between leg pain at rest and spinal nerve edema in symptomatic foraminal stenosis has not been reported., Hypothesis: The purpose of this prospective study is to reveal a correlation between leg pain at rest and spinal nerve edema focusing on the pathophysiology of symptomatic foraminal stenosis., Patients and Methods: Clinical findings and MRM findings were surveyed among 30 patients with symptomatic foraminal stenosis diagnosed by MR imaging (MRI) and selective nerve root block. Comparisons of patient characteristics and clinical findings between the prevalence and absence groups of spinal nerve edema on MRM were analyzed. A correlation between the visual analogue scale (VAS) for leg pain at rest and the spinal edema ratio calculated as maximum intensity value of the affected spinal nerve/maximum intensity value of the asymptomatic side from region of interest (ROI) made on MRM was evaluated., Results: Twenty symptomatic foraminal stenosis cases (67%) showed the affected spinal nerve edema on MRM. The prevalence and VAS of leg pain at rest were significantly higher in the presence of spinal nerve edema group (95% and 67.0±36.4, respectively). The correlation coefficient between the VAS for leg pain at rest (53.0±33.6) and the spinal nerve edema ratio (1.3±0.3) was 0.647 (p<0.01)., Discussion: Our study revealed the substantial correlation found between the spinal nerve edema ratio on MRM and the VAS for leg pain at rest in symptomatic foraminal stenosis. The correlation between spinal nerve edema and leg pain at rest has potential to clarify the pathology of symptomatic foraminal stenosis., Level of Evidence: IV., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Neuropathic pain can cause significant physical and economic burden, and there are no effective long-term treatments. We conducted a bioinformatics analysis to identify mechanisms to determine strategies for more effective treatments of neuropathic pain., Method: GSE24982 and GSE63442 microarray datasets were extracted from the Gene Expression Omnibus database to analyze transcriptome differences of neuropathic pain in the dorsal root ganglions (DRGs). We filtered the differentially expressed genes (DEGs) in the two datasets and conducted Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the shared DEGs. The Protein-Protein Interaction network was used to determine the hub genes, which were verified in the GSE30691 dataset. miRDB and miRWalk Databases were used to predict potential miRNA of the selected DEGs. We made the spinal nerve ligation (SNL) rat model and qPCR was used to verify the differential expression of hub genes., Results: A total of 182 overlapped DEGs were found between GSE24982 and GSE63442 datasets. The GO and KEGG analysis showed that the selected DEGs were enriched in infection, transmembrane transport of ion channels, and synaptic transmission. We identified seven hub genes (Atf3, Aif1, Ctss, Gfap, Scg2, Jun, and Vgf). qPCR verified the expression differences of the hub genes in the DRGs after SNL model. Predicted miRNA targeting each selected hub genes were identified., Conclusions: Seven hub genes related to the pathogenesis of neuropathic pain and potential targeting miRNA were identified, expanding understanding of the mechanism of neuropathic pain and facilitating treatment development., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Introduction: Percutaneous radiofrequency facet denervation (PRFD) by thermocoagulation is a useful treatment for nonspecific thoracic pain syndrome. To guarantee that maximal thermal lesion is applied to the nerve, it is essential to have precise knowledge of the topography of the thoracic dorsal branches of the spinal nerves. This special anatomy was investigated, and the results were compared with the existing technique for PRFD, where the active needle tip is placed in the junction of the superior articular process and the transverse process., Methods: Twenty thoracic spines of cadavers (10 females and 10 males) embalmed according to Thiel's method were bilaterally dissected. After careful removal of skin and subcutaneous fat tissue, the lateral and medial branches were traced centrally. In addition, the articular branch to the thoracic facet joint was traced peripherally. The distance of the medial branch to the inferior articular process at the level of the nerve passing the superior costotransverse ligament was measured., Results: The dorsal branch bifurcates into lateral and medial branches medial to the superior costotransverse ligament. The medial branch runs laterally first to pass in between two parts of the intertransverse ligament running dorsally and to turn medially superficial to this ligament. The zygapophysial branch always originated from the medial branch passing the inferior articular process laterally by running caudally to turn medially and send branches to the capsule of the zygapophyseal joint. The distance of the medial branch lateral to the inferior articular process was constantly 3 mm., Conclusions: The current technique of PRFD at the thoracic spine targets the medial branch distal to the separation of the articular branch, rendering the lesion ineffective at denervating the zygapophyseal joint. For selective thermocoagulation of the articular branches of the thoracic zygapophyseal joint, a new technique should be developed. We propose an anatomically informed needle position that can now be confirmed clinically., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Rami communicantes (RC) infiltration and radiofrequency lesions are new techniques for the treatment of discogenic low back pain (DLBP). Their efficacy is controversial, and the classification of RC remains unclear. We aimed to explore the differences between RC and reclassify RC according to their anatomical characteristics., Methods: Sixteen sides of the lumbar spine from eight adult male embalmed cadavers were dissected. The presence of RC was noted. The morphology, origin, distribution, course, quantity and spatial orientation of RC on the lumbar spine were examined. The length and width of the RC were measured by a caliper., Results: A total of 213 RC were found in the 8 cadavers in the lumbar region. RC were divided into three types: superficial rami (70, 32.86%), which penetrated the psoas major (PM) and ran above the aponeurosis of the PM; deep rami (125, 58.69%), which ran along the waist of the vertebral body beneath the aponeurosis of the PM; and discal rami, which ran over and adhered to the surface of the intervertebral disc. Superficial rami were divided into two subtypes: oblique rami (45, 21.13%) and parabolic rami (25, 11.74%), which crossed the vertebra and the disc in an oblique and a parabolic course, respectively., Conclusions: RC should play an important role in the innervation of the lumbar spine. Detailed knowledge of RC in the lumbar region may help surgeons improve the efficacy of infiltration and percutaneous radiofrequency as a supplementary treatment for DLBP., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Complete spinal cord injury (SCI) leads to permanent motor, sensitive and sensory deficits. In humans, there is currently no therapy to promote recovery and the only available treatments include surgical intervention to prevent further damage and symptomatic relief of pain and infections in the acute and chronic phases, respectively. Basically, the spinal cord is classically viewed as a nonregenerative tissue with limited plasticity. Thereby the establishment of the "glial" scar which appears within the SCI is mainly described as a hermetic barrier for axon regeneration. However, recent discoveries have shed new light on the intrinsic functional plasticity and endogenous recovery potential of the spinal cord. In this review, we will address the different aspects that the spinal cord plasticity can take on. Indeed, different experimental paradigms have demonstrated that axonal regrowth can occur even after complete SCI. Moreover, recent articles have demonstrated too that the "glial" scar is in fact composed of several cellular populations and that each of them exerts specific roles after SCI. These recent discoveries underline the underestimation of the plasticity of the spinal cord at cellular and molecular levels. Finally, we will address the modulation of this endogenous spinal cord plasticity and the perspectives of future therapeutic opportunities which can be offered by modulating the injured spinal cord microenvironment.

Electroacupuncture (EA) has been used to treat neuropathic pain induced by peripheral nerve injury (PNI) by applying an electrical current to acupoints with acupuncture needles. However, the mechanisms by which EA treats pain remain indistinct. High P2X4 receptor (P2X4R) expression levels demonstrate a notable increase in hyperactive microglia in the ipsilateral spinal dorsal horn following PNI. In order to demonstrate the possibility that EA analgesia is mediated in part by P2X4R in hyperactive microglia, the present study performed mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) tests in male Sprague‑Dawley rats that had undergone spinal nerve ligation (SNL). The expression levels of spinal P2X4R were determined using reverse transcription‑quantitative PCR, western blotting analysis and immunofluorescence staining. Furthermore, spontaneous excitatory postsynaptic currents (sEPSCs) were recorded using whole‑cell patch clamp to demonstrate the effect of EA on synaptic transmission in rat spinal substantia gelatinosa (SG) neurons. The results of the present study demonstrated that EA increased the MWT and TWL and decreased overexpression of P2X4R in hyperactive microglia in SNL rats. Moreover, EA attenuated the frequency of sEPSCs in SG neurons in SNL rats. The results of the present study indicate that EA may mediate P2X4R in hyperactive spinal microglia to inhibit nociceptive transmission of SG neurons, thus relieving pain in SNL rats.

Voltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel Na V 1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). When not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of Na V 1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2 K374A/K374A ) female mice have reduced Na V 1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2 K374A/K374A female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male CRMP2 K374A/K374A mice precipitated mechanical allodynia in mice otherwise resistant to developing persistent pain. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2 K374A/K374A mice. Finally, silencing these proteins in DRG neurons from female CRMP2 K374A/K374A mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non-SUMOylated CRMP2-mediated internalization of sodium channels in vivo.

Background: Dual diagnoses in genetics practice are not uncommon and patients with dual diagnosis often present with complex and challenging phenotypes. A combination of meticulous phenotyping and molecular genetic techniques are essential in solving these diagnostic odysseys., Methods: Clinical features and genetic workup of a patient presenting with incidental schwannomatosis., Results: A 19-year-old male presented with incidental painless schwannomatosis in the background of macrocephaly, distinctive facies, and learning disability. Comprehensive genetic testing with gene panel and chromosomal microarray led to a dual diagnosis of LZTR1-related schwannomatosis and 7q11.23 duplication syndrome., Conclusion: We emphasize the need for high index of suspicion and comprehensive genetic testing in complex phenotypes. Interrogation of the interplay between the pathogenic variants in multiple genes could improve our understanding of the pathophysiologic pathways and contribute to therapeutic discoveries., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Neuropathic pain is a severe problem that is difficult to treat clinically. Reducing abnormal remodeling of dendritic spines/synapses and increasing the anti-inflammatory effects in the spinal cord dorsal horn are potential methods to treat this disease. Previous studies have reported that electroacupuncture (EA) could increase the pain threshold after peripheral nerve injury. However, the underlying mechanism is unclear. P2X7 receptors (P2X7R) mediate the activation of microglia and participate in the occurrence and development of neuropathic pain. We hypothesized that the effects of EA on relieving pain may be related to the downregulation of the P2X7R. Spinal nerve ligation (SNL) rats were used as a model in this experiment, and 2'(3')-O-(4-benzoyl)benzoyl ATP (BzATP) was used as a P2X7R agonist. We found that EA treatment decreased dendritic spine density, inhibited synaptic reconstruction and reduced inflammatory response, which is consistent with the decrease in P2X7R expression as well as the improved neurobehavioral performance. In contrast to the beneficial effects of EA, BzATP enhanced abnormal remodeling of dendritic spines/synapses and inflammation. Furthermore, the EA-mediated positive effects were reversed by BzATP, which is consistent with the increased P2X7R expression. These findings indicated that EA improves neuropathic pain by reducing abnormal dendritic spine/synaptic reconstruction and inflammation via suppressing P2X7R expression.

Summary: In an ongoing effort to understand the pathogenesis of occipital neuralgia/headache/migraine, it is critical to describe the anatomical/tissue changes encountered during surgery. Greater occipital nerve anatomical studies mainly focus on the greater occipital nerve course through muscle/fascial planes and interaction with the occipital vessels. However, structural soft-tissue changes have not been described in detail. Anecdotally, trapezius fascia is thickened at the greater occipital nerve trigger site. This study further investigates this observation. Patients undergoing greater occipital nerve decompression surgery were enrolled prospectively in this observational study (n = 92). Tissue changes were recorded intraoperatively. The resulting data were examined. Trapezius fascia was more than 3 mm thick and appeared fibrotic in 86 patients (94 percent), whereas semispinalis muscle appeared normal in all subjects. The greater occipital nerve was macroscopically abnormal, defined as edematous, flattened, and discolored in 29 cases (32 percent). The occipital artery interacted significantly with the greater occipital nerve in 88 percent of cases. The authors conclude that the tissue structure is abnormal in patients undergoing greater occipital nerve decompression surgery. This is the first study that describes the prevalence of thickened and fibrotic appearing trapezius fascia at the occipital trigger site, a phenomenon encountered in the vast majority of patients (94 percent). This structural anomaly has a resemblance to thickened fascial tissues seen in other nerve compression syndromes, and could be related to microtrauma/overuse or actual trauma in the head and neck region., Competing Interests: Disclosure:The authors have no conflicts of interest to disclose. None of the authors has a financial interest in any of the products or devices mentioned in this article., (Copyright © 2020 by the American Society of Plastic Surgeons.)

Overexpression of Ca v 3.2 T-type Ca 2+ channels in L4 dorsal root ganglion (DRG) participates in neuropathic pain after L5 spinal nerve cutting (L5SNC) in rats. The L5SNC-induced neuropathic pain also involves high mobility group box 1 (HMGB1), a damage-associated molecular pattern protein, and its target, the receptor for advanced glycation end-products (RAGE). We thus studied the molecular mechanisms for the L5SNC-induced Ca v 3.2 overexpression as well as neuropathic pain in rats by focusing on; 1) possible involvement of early growth response 1 (Egr-1), known to regulate transcriptional expression of Ca v 3.2, and ubiquitin-specific protease 5 (USP5) that protects Ca v 3.2 from proteasomal degradation, and 2) possible role of HMGB1/RAGE as an upstream signal. Protein levels of Ca v 3.2 as well as Egr-1 in L4 DRG significantly increased in the early (day 6) and persistent (day 14) phases of neuropathy after L5SNC, while USP5 protein in L4 DRG did not increase on day 6, but day 14. An anti-HMGB1-neutralizing antibody or a low molecular weight heparin, a RAGE antagonist, prevented the development of neuropathic pain and upregulation of Egr-1 and Ca v 3.2 in L4 DRG after L5SNC. L5SNC increased macrophages accumulating in the sciatic nerves, and the cytoplasm/nuclear ratio of immunoreactive HMGB1 in those macrophages. Our findings suggest that L5SNC-induced Ca v 3.2 overexpression in L4 DRG and neuropathic pain involves Egr-1 upregulation downstream of the macrophage-derived HMGB1/RAGE pathway, and that the delayed upregulation of USP5 might contribute to the persistent Ca v 3.2 overexpression and neuropathy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Fluoroscopy-guided blockade of the greater occipital nerve (GON) is an accepted method for treating the symptoms of cervicogenic headaches (CGHs). However, the spread patterns among different injectate volumes of fluoroscopy-guided GON blocks are not well defined., Objective: A cadaveric study was established to determine the spread patterns of different volumes of dye injectate within a fluoroscopic GON block. Study Design . Cadaveric study. Setting . Xingtai Institute of Orthopaedics; Orthopaedic Hospital of Xingtai., Methods: 15 formalin-fixed cadavers with intact cervical spines were randomized in a 1 : 1 : 1 ratio to receive a fluoroscopy-guided GON injection of a 2, 3.5, or 5 ml volume of methylene blue. The suboccipital regions were dissected to investigate nerve involvement., Results: The suboccipital triangle regions, including the suboccipital nerves and GONs, were deeply stained in all cadavers. The third occipital nerve (TON) was stained in 7 of 10 administered 2 ml injections and in all the 3.5 ml and 5 ml injections. Compared to the 3 ml injectate group, the 5 mL cohort consistently saw injectate spreading to both superficial and distant muscles. Limitations . Given that cadavers were used in this study, cadaveric soft tissue composition and architecture can potentially become distorted and consequently affect injectate diffusion., Conclusions: A 3.5 or 5 mL fluoroscopy-guided GON injection of methylene blue successfully stains the GON, TON, and suboccipital nerves. This suggests that such an injection would generate blockade of all three nerve groups, which may contribute to the efficacy of the block for CGH. A volume of 3.5 ml may be enough for the performance of a fluoroscopy-guided GON block for therapeutic purposes., Competing Interests: All the authors declare that they have no conflicts of interest., (Copyright © 2020 Zhanfeng Song et al.)

Previous studies have shown that the peripheral nerve regeneration process is linked to pain in several neuropathic pain models. Other studies show that sympathetic blockade may relieve pain in some pain models and clinical conditions. This study examined reduction in peripheral nerve regeneration as one possible mechanism for relief of neuropathic pain by sympathetic blockade. A "microsympathectomy," consisting of cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, reduced mechanical hypersensitivity in 2 different rat neuropathic pain models. In the spinal nerve ligation model, in which some functional regeneration and reinnervation of the ligated spinal nerve can be observed, microsympathectomy reduced functional and anatomical measures of regeneration as well as expression of growth-associated protein 43 (GAP43), a regeneration-related protein. In the spared nerve injury model, in which functional reinnervation is not possible and the futile regeneration process results in formation of a neuroma, microsympathectomy reduced neuroma formation and GAP43 expression. In both models, microsympathectomy reduced macrophage density in the sensory ganglia and peripheral nerve. This corroborates previous work showing that sympathetic nerves may locally affect immune function. The results further highlight the challenge of improving pain in neuropathic conditions without inhibiting peripheral nerve regeneration that might otherwise be possible and desired.

Activation of CX3CR1 in microglia plays an important role in the development of neuropathic pain. Here, we investigated whether neuropathic pain could be attenuated in spinal nerve ligation (SNL)-induced rats by reducing microglial activation through the use of poly(D,L-lactic-co-glycolic acid) (PLGA)-encapsulated CX3CR1 small-interfering RNA (siRNA) nanoparticles. After confirming the efficacy and specificity of CX3CR1 siRNA, as evidenced by its anti-inflammatory effects in lipopolysaccharide-stimulated BV2 cells in vitro, PLGA-encapsulated CX3CR1 siRNA nanoparticles were synthesized by sonication using the conventional double emulsion (W/O/W) method and administered intrathecally into SNL rats. CX3CR1 siRNA-treated rats exhibited significant reductions in the activation of microglia in the spinal dorsal horn and a downregulation of proinflammatory mediators, as well as a significant attenuation of mechanical allodynia. These data indicate that the PLGA-encapsulated CX3CR1 siRNA nanoparticles effectively reduce neuropathic pain in SNL-induced rats by reducing microglial activity and the expression of proinflammatory mediators. Therefore, we believe that PLGA-encapsulated CX3CR1 siRNA nanoparticles represent a valuable new treatment option for neuropathic pain.

Pontocerebellar Hypoplasia type 1 is a rare heterogeneous neurodegenerative disorder with multiple subtypes linked to dysfunction of the exosome complex. Patients with mutations in exosome subunits exhibit a generally lethal phenotype characterized by cerebellar and pontine hypoplasia in association with spinal motor neuropathy and multiple systemic and neurologic features. Recently, two variants in the novel PCH1 associated protein EXOSC9 p.(Leu14Pro) and p.(Arg161*) have been identified in 4 unrelated patients exhibiting a severe phenotype involving cerebellar hypoplasia, axonal motor neuropathy, hypotonia, feeding difficulties, and respiratory insufficiency (PCH1D). We report clinical and molecular characterization of 2 unrelated patients exhibiting a relatively milder phenotype involving hypotonia, brachycephaly, cerebellar atrophy, psychomotor delay, as well as lactic acidosis and aberrant CNS myelination, resulting from the recurring homozygous missense mutation NM&#95;001034194.1: c.41T>C; p.(Leu14Pro) in the EXOSC9 gene. We review the clinical picture of the EXOSC9-related PCH disorder., (Copyright © 2019. Published by Elsevier Masson SAS.)

Fibroblast growth factor-inducible-14 (Fn14), a receptor for tumor necrosis-like weak inducer of apoptosis, is expressed in the neurons of dorsal root ganglion (DRG). Its mRNA is increased in the injured DRG following peripheral nerve injury. Whether this increase contributes to neuropathic pain is unknown. We reported here that peripheral nerve injury caused by spinal nerve ligation (SNL) increased the expression of Fn14 at both protein and mRNA levels in the injured DRG. Blocking this increase attenuated the development of SNL-induced mechanical, thermal, and cold pain hypersensitivities. Conversely, mimicking this increase produced the increases in the levels of phosphorylated extracellular signal-regulated kinase ½ and glial fibrillary acidic protein in ipsilateral dorsal horn and the enhanced responses to mechanical, thermal, and cold stimuli in the absence of SNL. Mechanistically, the increased Fn14 activated the NF-κB pathway through promoting the translocation of p65 into the nucleus of the injured DRG neurons. Our findings suggest that Fn14 may be a potential target for the therapeutic treatment of peripheral neuropathic pain.

Background: Previous studies have demonstrated that the CXCL12/CXCR4 signaling axis is involved in the regulation of neuropathic pain (NP). Here, we performed experiments to test whether the CXCL12/CXCR4 signaling pathway contributes to the pathogenesis of neuropathic pain after spinal nerve ligation (SNL) via central sensitization mechanisms., Methods: Neuropathic pain was induced and assessed in a SNL rat model. The expression and distribution of CXCL12 or CXCR4 were examined by immunofluorescence staining and western blot. The effects of CXCL12 rat peptide, CXCL12 neutralizing antibody, CXCR4 antagonist, and astrocyte metabolic inhibitor on pain hypersensitivity were explored by behavioral tests in naive or SNL rats. We measured the expression level of c-Fos and CGRP to evaluate the sensitization of neurons by RT-PCR. The activation of astrocyte and microglia was analyzed by measuring the level of GFAP and iba-1. The mRNA levels of the pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6 and Connexin 30, Connexin 43, EAAT 1, EAAT 2 were also detected by RT-PCR., Results: First, we found that the expression of CXCL12 and CXCR4 was upregulated after SNL. CXCL12 was mainly expressed in the neurons while CXCR4 was expressed both in astrocytes and neurons in the spinal dorsal horn after SNL. Moreover, intrathecal administration of rat peptide, CXCL12, induced hypersensitivity in naive rats, which was partly reversed by fluorocitrate. In addition, the CXCL12 rat peptide increased mRNA levels of c-Fos, GFAP, and iba-1. A single intrathecal injection of CXCL12 neutralizing antibody transiently reversed neuropathic pain in the SNL rat model. Consecutive use of CXCL12 neutralizing antibody led to significant delay in the induction of neuropathic pain, and reduced the expression of GFAP and iba-1 in the spinal dorsal horn. Finally, repeated intrathecal administration of the CXCR4 antagonist, AMD3100, significantly suppressed the initiation and duration of neuropathic pain. The mRNA levels of c-Fos, CGRP, GFAP, iba-1, and pro-inflammatory cytokines, also including Connexin 30 and Connexin 43 were decreased after injection of AMD3100, while EAAT 1 and EAAT 2 mRNAs were increased., Conclusion: We demonstrate that the CXCL12/CXCR4 signaling pathway contributes to the development and maintenance of neuropathic pain via central sensitization mechanisms. Importantly, intervening with CXCL12/CXCR4 presents an effective therapeutic approach to treat the neuropathic pain., (© 2019 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.)

The role of the voltage-gated sodium channel 1.7 (Nav1.7) is unclear in models of neuropathic pain induced by nerve injury. In the present study, we measured expression levels of Nav1.7 in two distinct neuropathic pain models: spinal nerve ligation (SNL) and chronic constriction injury (CCI). In the SNL model, both mRNA and protein levels of Nav1.7 were markedly lower in the L5 dorsal root ganglia (DRG) but were significantly higher in the L4 DRG. Nav1.7 protein levels were notably higher in both L4 and L5 DRGs under CCI conditions. We found that excessive damage of L5 nerves such as SNL reduced expression levels of Nav1.7 in the injured L5 DRG and activated the adjacent uninjured DRG, resulting in Nav1.7 level increases in the adjacent L4 DRG. We confirmed again that Nav1.7 was closely related to neuropathic pain induced by nerve injury. More importantly, our results suggest that tracing the molecular changes exclusively in the L5 DRG in SNL model may not completely explain the pain mechanism; it is necessary to study the adjacent uninjured L4 DRG., (© 2019 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Purpose: This study was performed to determine the dose-related incidence of neuropathy from single-session irradiation of the C6-C8 spinal nerves using a pig model and to test the hypothesis that the spinal nerves and spinal cord have the same tolerance to full cross-sectional irradiation., Methods and Materials: Twenty-five Yucatan minipigs received study treatment. Each animal underwent computed tomography and magnetic resonance imaging for treatment planning, followed by single-session stereotactic ablative radiation therapy. A 1.5-cm length of the left-sided C6, C7, and C8 spinal nerves was targeted. Pigs were distributed into 5 groups with prescription doses of 16 (n = 7), 18 (5), 20 (5), 22 (5), or 24 (3) Gy with corresponding maximum nerve doses of 17.3, 19.5, 21.6, 24.1, and 26.2 Gy. The neurologic status of all animals was followed for approximately 52 weeks by serial electrodiagnostic examination and daily observation of gait. Histopathologic examination of paraffin-embedded sections with Luxol fast blue/periodic acid-Schiff staining was performed on bilateral spinal nerves and the spinal cord., Results: Marked gait change was observed in 15 of the 25 irradiated pigs. Affected animals presented with a limp in their left front limb, and electromyography demonstrated evidence of denervation in C6 and C7 innervated muscles. Probit analysis showed the ED 50 for gait change after irradiation of the spinal nerves to be 19.7 Gy (95% confidence interval, 18.5-21.1). The latency for all responding pigs was 9 to 15 weeks after irradiation. All symptomatic pigs had demyelination and fibrosis in their irradiated nerves, whereas contralateral nerves and spinal cord were normal., Conclusions: The ED 50 for symptomatic neuropathy after full cross-sectional irradiation of the spinal nerves was found to be 19.7 Gy. The dose response of the C6-C8 spinal nerves is not significantly different from that of full cross-sectional irradiation of the spinal cord as observed in companion studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: The middle cluneal nerves (MCNs) are stated to arise from the sacral dorsal rami of S1 to S3 and supply the gluteal skin, but their detailed anatomy is unclear and often variably depicted and described. Therefore, the goal of this study was to revisit the anatomy of the MCNs and provide a clearer picture of their morphology., Methods: Five fresh-frozen Caucasian cadavers (10 sides) (2 men and 3 women) were dissected for this study. The sacral dorsal rami from each posterior sacral foramen were identified and traced laterally to identify the MCNs. The contribution, pathway, and distribution of the MCNs were investigated., Results: Each sacral dorsal ramus joined to form the posterior sacrococcygeal plexus. A total of 25 MCNs were identified. The MCNs were formed by the sacral dorsal rami of S1-2 in 48% (12/25), S1-3 in 4% (1/25), S1-4 in 20% (5/25), S2-3 in 8% (2/25), and S2-4 in 20% (5/25). The MCNs pierced the gluteus maximus by 2 different pathways and supplied the gluteal skin or the gluteus maximus muscle., Conclusions: We clarified the anatomy and variations of the MCNs and revisited its current nomenclature. Such knowledge might improve diagnoses and invasive procedure outcomes in patients with pathology in the region of the MCNs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

After spine fusion surgery, it is difficult to evaluate the spinal canal and nerve roots using magnetic resonance imaging (MRI) because of metallic implant-related artifacts. Digital tomosynthesis is a new radiographic technique that can acquire tomographic images with reduced metallic artifact effects compared with MRI. We report a case demonstrating the visualization of nerve roots nearby metallic implants using dynamic tomosynthesis-radiculography (DTRG) after spinal fusion surgery. A 77-year-old man, who 3 years earlier underwent spine fusion surgery at L3-L5, presented complaining of newly-onset low back pain and radicular symptoms in the right fifth lumbar (L5) nerve root area. His symptoms were exacerbated when he stood upright. We suspected right L5 nerve root radiculopathy, but MRI could not depict any lesion of the nerve root because of metallic implant-related artifacts. We performed DTRG at the right L5 nerve root with the patient in both prone and upright positions. The right L5 nerve root was detected clearly, and nerve root compression at the foramina when the patient was upright was exacerbated more than when the patient was in a prone position. DTRG is helpful to diagnose lumbar foraminal stenosis nearby metallic implants after spine fusion surgery., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Microglia play a critical role in neuropathic pain. Since upregulated Foxp3 in microglia enhances tissue repair by resolving neuroinflammation in excitotoxin-induced neuronal death, it may attenuate neuropathic pain in a similar manner. Therefore, this study tests whether Foxp3 introduced with poly (D, L-lactic-co-glycolic acid) (PLGA) nanoparticles (Foxp3 NPs) can alleviate neuropathic pain by inhibiting microglia activity. The prepared Foxp3 NPs had an anti-inflammatory effect on lipopolysaccharide-stimulated BV2 cells in vitro, and localized to spinal microglia in vivo. Further, the Foxp3 NPs significantly attenuated pain behavior induced by spinal nerve ligation in rats for 7 days by suppressing microglial activity, followed by the downregulation of pro-nociceptive genes and the upregulation of anti-nociceptive genes in the spinal dorsal horn. Collectively, these data suggest that Foxp3 NPs effectively relieve neuropathic pain in animals by reducing microglia activity and subsequent modulation of neuroinflammation, and may be of therapeutic value in the treatment of neuropathic pain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The therapeutic benefit of nerve decompression surgeries for chronic headache/migraine are controversial., Aim: To provide clinical characteristics of headache type and treatment outcome of occipital nerve decompression surgery., Methods: A retrospective review of clinical records. Inclusion criteria were evidence of chronic occipital headache with and without migrainous features and tenderness of neck muscles, occipital allodynia, and inadequate response to prophylactic drugs., Results: Surgical decompression of the greater and lesser occipital nerves provided complete and extended (3-6 years) relief of new daily persistent headache in case 3 (46 year old female), and of chronic post-traumatic headache in cases 4 and 6 (35 and 30 year old females, respectively), partial relief of chronic headache/migraine in cases 1 and 2 (41 year old female and 36 year old male), and no relief of episodic (cases 3 and 4) or chronic migraine (case 5, 52 year old male), or chronic tension-type headache (case 7, 31 year old male)., Conclusions: As a case series, this study cannot test a hypothesis or determine cause and effect. However, the complete elimination of new daily persistent headache and post-traumatic headache, and the partial elimination of chronic headache/migraine in two patients - all refractory to other treatment approaches - supports and justifies the effort to continue to generate data that can help determine whether decompression nerve surgeries are beneficial in the treatment of certain types of chronic headache.

Neuropathic pain is a well-known type of chronic pain caused by damage to the nervous system. Autophagy is involved in the development and/or progression of many diseases, including neuropathic pain. Emerging evidence suggests that metformin relieves neuropathic pain in several neuropathic pain models; however, metformin's cellular and molecular mechanism for pain relief remains unknown. In this study, we investigated the therapeutic effects of metformin on pain relief after spinal nerve ligation (SNL) and its underlying mechanism of autophagy regulation. Behavioural analysis, histological assessment, expression of c-Fos and molecular biological changes, as well as ultrastructural features, were investigated. Our findings showed that the number of autophagosomes and expression of autophagy markers, such as LC3 and beclin1, were increased, while the autophagy substrate protein p62, as well as the ubiquitinated proteins, were accumulated in the ipsilateral spinal cord. However, metformin enhanced the expression of autophagy markers, while it abrogated the abundance of p62 and ubiquitinated proteins. Blockage of autophagy flux by chloroquine partially abolished the apoptosis inhibition and analgesic effects of metformin on SNL. Taken together, these results illustrated that metformin relieved neuropathic pain through autophagy flux stimulation and provided a new direction for metformin drug development to treat neuropathic pain., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Increasing evidence indicates that pattern recognition receptors (PRRs) are involved in neuropathic pain after peripheral nerve injury (PNI). While a significant number of studies support an association between neuropathic pain and the innate immune response mediated through Toll-like receptors, a family of PRRs, the roles of other types of PRRs are largely unknown. In this study, we have focused on the macrophage-inducible C-type lectin (Mincle), a PRR allocated to the C-type lectin receptor family. Here, we show that Mincle is involved in neuropathic pain after PNI. Mincle-deficient mice showed impaired PNI-induced mechanical allodynia. After PNI, expression of Mincle mRNA was rapidly increased in the injured spinal nerve. Most Mincle-expressing cells were identified as infiltrating leucocytes, although the migration of leucocytes was also observed in Mincle-deficient mice. Furthermore, Mincle-deficiency affected the induction of genes, which are reported to contribute to neuropathic pain after PNI in the dorsal root ganglia and spinal dorsal horn. These results suggest that Mincle is involved in triggering sequential processes that lead to the pathogenesis of neuropathic pain.

Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation rat model. After establishment of spinal nerve ligation rat models, rats were infected with adeno-associated virus-neurofilament light polypeptide, adeno-associated virus-miR-7a or treated with metformin. The paw withdrawal threshold and paw withdrawal latency were assessed afterward, and the expression of miR-7a and neurofilament light polypeptide as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of neurofilament light polypeptide on neuropathic pain was detected using plasmid overexpressing neurofilament light polypeptide. Spinal nerve ligation rat model exhibited upregulation of neurofilament light polypeptide but downregulation of miR-7a. In addition, neurofilament light polypeptide accumulation or miR-7a inhibition decreased paw withdrawal threshold and paw withdrawal latency. Then, neurofilament light polypeptide accumulation or miR-7a inhibition was observed to increase the phosphorylation level of signal transducer and activator of transcription. miR-7a was found to directly target neurofilament light polypeptide and downregulate neurofilament light polypeptide. In addition, inhibiting the signal transducer and activator of transcription signaling pathway was also revealed to increase paw withdrawal threshold and paw withdrawal latency. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the signal transducer and activator of transcription signaling pathway by repressing neurofilament light polypeptide. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.

Objective: The aim of this study was to investigate the anatomy of the superior cluneal nerves more proximal to the posterior layer of the thoracolumbar fascia., Methods: Twelve sides of 6 fresh-frozen cadavers were used. The age at death ranged from 54 to 88 years. After a transverse skin incision 10 mm above the iliac crest, the superior cluneal nerves were detected by blunt dissection and traced back to the dorsal root ganglia. The diameter of the nerves from L1 to L3 was measured. Also, the relationship to the erector spinae muscle and dorsal ramus was recorded., Results: The mean diameters of the origin of the L1, L2, and L3 were 1.71 ± 0.29 mm, 1.73 ± 0.40 mm, and 1.52 ± 0.55 mm, respectively. On 7 sides (58.3%) for L1, seven sides (58.3%) for L2, and 10 sides (83.3%) for L3, the nerves pierced the iliocostalis muscle. One side (8.3%) for L2 and one (8.3%) for L3 had no cutaneous branch., Conclusions: The results of this study could help to elucidate the anatomy of the superior cluneal nerves and help avoid complications during surgical approaches to the lumbar spine., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Objectives: Erector spinae block is an ultrasound-guided interfascial plane block first described in 2016. The objectives of this cadaveric dye injection and dissection study were to simulate an erector spinae block to determine if dye would spread anteriorly to the involve origins of the ventral and dorsal branches of the spinal nerves., Methods: In 10 unembalmed human cadavers, 20 mL of 0.25% methylene blue dye was injected bilaterally into the plane between the fifth thoracic transverse process and erector spinae muscle. An in-plane ultrasound-guided technique with the transducer orientated longitudinally was used. During dissection, superficial and deep muscles were identified, and extent of dye spread was documented in cephalocaudal and lateral directions. The ventral and dorsal rami of spinal nerves and dorsal root ganglion at each level were examined to determine if they were stained by dye., Results: There was extensive cephalocaudad and lateral spread of dye deep and superficial to the erector spinae muscles. Except for 1 injection (from 20), the ventral rami were not stained by the dye. In only 2 injections did the dye track posteriorly through the costotransverse foramen to the dorsal root ganglion. In all other cases, the dorsal root ganglia were not involved in the dye injection. The dye stained the dorsal rami posterior to the costotransverse foramen., Conclusions: There was no spread of dye anteriorly to the paravertebral space to involve origins of the ventral and dorsal branches of the thoracic spinal nerves. Dorsal ramus involvement was posterior to the costotransverse foramen.

Peripheral nerve injury induces neuropathic pain, which is characterized by the tactile allodynia and thermal hyperalgesia. N-type voltage-dependent Ca 2+ channel (VDCC) plays pivotal roles in the development of neuropathic pain, since mice lacking Ca v 2.2, the pore-forming subunit of N-type VDCC, show greatly reduced symptoms of both tactile allodynia and thermal hyperalgesia. Our study on gene expression profiles of the wild-type and N-type VDCC knockout (KO) spinal cord and several pain-related brain regions after spinal nerve ligation (SNL) injury revealed altered expression of genes encoding catalytic subunits of phosphatidylinositol-3 kinase (PI3K). PI3K/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling is considered to be very important for cancer development and drugs targeting the molecules in this pathway have been tested in oncology trials. In the present study, we have tested whether the changes in expression of molecules in this pathway in mice having spinal nerve injury are causally related to neuropathic pain. Our results suggest that spinal nerve injury induces activation of N-type VDCC and the following Ca 2+ entry through this channel may change the expression of genes encoding PI3K catalytic subunits (p110α and p110γ), Akt, retinoid X receptor α (RXRα) and RXRγ. Furthermore, the blockers of the molecules in this pathway are found to be effective in reducing neuropathic pain both at the spinal and at the supraspinal levels. Thus, the activation of PI3K/Akt/mTOR/peroxisome proliferator activated receptor gamma (PPARγ) pathway would be a hallmark of the induction and maintenance of neuropathic pain., (Copyright © 2018 Elsevier Inc. All rights reserved.)

As reliable biomarkers of disease activity are lacking, monitoring of therapeutic response in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains a challenge. We sought to determine whether nerve ultrasound and electrophysiology scoring could close this gap. In CIDP patients (fulfilling EFNS/PNS criteria), we performed high-resolution nerve ultrasound to determine ultrasound pattern sum scores (UPSS) and predominant echotexture nerve conduction study scores (NCSS) as well as Medical Research Council sum scores (MRCSS) and inflammatory neuropathy cause and treatment disability scores (INCAT) at baseline and after 12 months of standard treatment. We retrospectively correlated ultrasound morphology with nerve histology when available. 72/80 CIDP patients featured multifocal nerve enlargement, and 35/80 were therapy-naïve. At baseline, clinical scores correlated with NCSS (r 2  = 0.397 and r 2  = 0.443, p < 0.01), but not or hardly with UPSS (Medical Research Council sum scores MRCSS r 2  = 0.013, p = 0.332; inflammatory neuropathy cause and treatment disability scores INCAT r 2  = 0.053, p = 0.048). Longitudinal changes in clinical scores, however, correlated significantly with changes in both UPSS and NCSS (r 2  = 0.272-0.414, p < 0.0001). Combining nerve/fascicle size with echointensity and histology at baseline, we noted 3 distinct classes: 1) hypoechoic enlargement, reflecting active inflammation and onion bulbs; 2) nerve enlargement with additional hyperechogenic fascicles/perifascicular tissue in > 50% of measured segments, possibly reflecting axonal degeneration; and 3) almost no enlargement, reflecting "burned-out" or "cured" disease without active inflammation. Clinical improvement after 12 months was best in patients with pattern 1 (up to 75% vs up to 43% in pattern 2/3, Fisher's exact test p < 0.05). Nerve ultrasound has additional value not only for diagnosis, but also for classification of disease state and may predict treatment response.

Abnormal cranial or spinal nerve contrast enhancement on MRI in cases of suspected pediatric leukodystrophy is recognized as an important clue to the diagnosis of either metachromatic leukodystrophy or globoid cell leukodystrophy (Krabbe disease). We report a case of genetically confirmed childhood vanishing white matter with enhancement of multiple cranial and spinal nerves in addition to the more typical intracranial findings. This case expands the limited differential diagnosis of cranial nerve or spinal nerve enhancement in cases of suspected leukodystrophy and may aid in more efficient work-up and earlier diagnosis of vanishing white matter.

Neuropathic pain is a complex, chronic pain state characterized by hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence has indicated that the microglial Toll-like receptor 4 (TLR4) and autophagy are implicated in neurodegenerative diseases, but their relationship and role in neuropathic pain remain unclear. In this study, we examined TLR4 and its association with autophagic activity using a chronic constriction injury (CCI)-induced neuropathic pain model in wild-type (WT) and TLR4-knockout (KO) mice. The mice were assigned into four groups: WT-Contralateral (Contra), WT-Ipsilateral (Ipsi), TLR4 KO-Contra, and TLR4 KO-Ipsi. Behavioral and mechanical allodynia tests and biochemical analysis of spinal cord tissue were conducted following CCI to the sciatic nerve. Compared with the Contra group, mechanical allodynia in both the WT- and TLR4 KO-Ipsi groups was significantly increased, and a marked decrease of allodynia was observed in the TLR4 KO-Ipsi group. Although glial cells were upregulated in the WT-Ipsi group, no significant change was observed in the TLR4 KO groups. Moreover, protein expression and immunoreactive cell regulation of autophagy (Beclin 1, p62) were significantly increased in the neurons, but not microglia, of WT-Ipsi group compared with the WT-Contra group. The level of PINK1, a marker for mitophagy was increased in the neurons of WT, but not in TLR4 KO mice. Together, these results show that TLR4-mediated p62 autophagic impairment plays an important role in the occurrence and development of neuropathic pain. And what is more, microglial TLR4-mediated microglial activation might be indirectly coupled to neuronal autophage.

Neuropathic pain is caused by peripheral nerve injury (PNI). One hallmark symptom is allodynia (pain caused by normally innocuous stimuli), but its mechanistic underpinning remains elusive. Notably, whether selective stimulation of non-nociceptive primary afferent Aβ fibers indeed evokes neuropathic pain-like sensory and emotional behaviors after PNI is unknown, because of the lack of tools to manipulate Aβ fiber function in awake, freely moving animals. In this study, we used a transgenic rat line that enables stimulation of non-nociceptive Aβ fibers by a light-activated channel (channelrhodopsin-2; ChR2). We found that illuminating light to the plantar skin of these rats with PNI elicited pain-like withdrawal behaviors that were resistant to morphine. Light illumination to the skin of PNI rats increased the number of spinal dorsal horn (SDH) Lamina I neurons positive to activity markers (c-Fos and phosphorylated extracellular signal-regulated protein kinase; pERK). Whole-cell recording revealed that optogenetic Aβ fiber stimulation after PNI caused excitation of Lamina I neurons, which were normally silent by this stimulation. Moreover, illuminating the hindpaw of PNI rats resulted in activation of central amygdaloid neurons and produced an aversion to illumination. Thus, these findings provide the first evidence that optogenetic activation of primary afferent Aβ fibers in PNI rats produces excitation of Lamina I neurons and neuropathic pain-like behaviors that were resistant to morphine treatment. This approach may provide a new path for investigating circuits and behaviors of Aβ fiber-mediated neuropathic allodynia with sensory and emotional aspects after PNI and for discovering novel drugs to treat neuropathic pain.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by cell death of upper and lower motor neurons (MNs). The cause of MN cell loss is not completely understood but involves both cell autonomous and non-cell autonomous mechanisms. Numerous molecules have been implicated to be involved in the death of MNs. One such candidate is semaphorin 3A (Sema3A). In ALS patients, Sema3A was shown to be significantly upregulated in the motor cortex and downregulated in the spinal cord. In the mouse, Sema3A was shown to be an axon repellent molecule for MNs. Sema3A could also induce death of different neuronal types that are also repelled by it, including sensory, sympathetic, retinal, and cortical neurons. In contrast, astrocyte-specific knockout of Sema3A results in motor neuron cell death, consistent with the idea that Sema3A is a survival factor for mouse motor neurons. Here, we tested the response of human cortical neurons and spinal cord MNs to Sema3A. We found that Sema3A enhances the survival of spinal cord MNs. In contrast, Sema3A reduces the survival of cortical neurons. Thus, both upregulation of Sema3A in the cortex, or downregulation in the spinal cord of ALS patients is likely to directly contribute to MNs cell loss in ALS patients.

High-resolution ultrasound (US) enables prompt depiction of muscles, tendons, ligaments, and peripheral nerves. It seems to be the best imaging modality for guiding perineural injections. The most complicated neurovascular network of the musculoskeletal system surrounds the cervical spine; so injection to that region is never an easy task. This article elaborates the regional anatomy and the use of US scanning and guidance for cervical interventions; for example, cervical root, superficial cervical plexus, stellate ganglion, cervical medial branch, greater occipital nerve, and third occipital nerve. The article aims to lead readers to practice US-guided cervical injections precisely and safely., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Previous studies have demonstrated that microRNAs (miRNAs) play important roles in the pathogenesis of neuropathic pain. In the present study, we found that miR-32-5p was significantly upregulated in rats after spinal nerve ligation (SNL), specifically in the spinal microglia of rats with SNL. Functional assays showed that knockdown of miR-32-5p greatly suppressed mechanical allodynia and heat hyperalgesia, and decreased inflammatory cytokine (IL-1β, TNF-α and IL-6) protein expression in rats after SNL. Similarly, miR-32-5p knockdown alleviated cytokine production in lipopolysaccharide (LPS)-treated spinal microglial cells, whereas its overexpression had the opposite effect. Mechanistic investigations revealed Dual-specificity phosphatase 5 (Dusp5) as a direct target of miR-32-5p, which is involved in the miR-32-5p-mediated effects on neuropathic pain and neuroinflammation. We demonstrated for the first time that miR-32-5p promotes neuroinflammation and neuropathic pain development through regulation of Dusp5. Our findings highlight a novel contribution of miR-32-5p to the process of neuropathic pain, and suggest possibilities for the development of novel therapeutic options for neuropathic pain., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Replantation of the avulsed nerve root has been proposed for the treatment of severe brachial plexus injury for several decades. However, due to the complexity of the technique and limited functional improvement, practical applications are yet to be implemented., Objective: In the present study, we investigated the effect of pretreatment with resveratrol on nerve autografts used for replantation surgery in a rat model of nerve root avulsion., Methods: Resveratrol pretreatment was performed using an explant culture technique. Two surgical procedures were performed. During the first surgery, Sprague-Dawley rats were subjected to left C6 nerve root avulsion, and nerves were harvested for autografting. The harvested grafts were explant-cultured for 1 week. A second procedure was performed to replant the C6 nerve root using the explant-cultured nerve graft 1 week after the first procedure. Histological and immunohistochemical analyses were performed 8 weeks after the second procedure. We first compared findings between explant-cultured nerve grafts and fresh nerve grafts, following which we compared findings between explant-cultured grafts pretreated with and without resveratrol. Changes induced within nerve grafts by 1 week of explant culture with or without resveratrol were investigated in vitro., Results: There was no significant difference in outcomes between 1 week-explant-cultured and fresh nerve grafts. Addition of resveratrol to the explant culture medium resulted in a significant increase in the number and myelin thickness of regenerated axons, and in the number of regenerating motor neurons in the C6 spinal cord segment. In vitro analyses revealed that nerve grafts pretreated with resveratrol exhibited significant increases in glial cell line-derived neurotrophic factor (GDNF) expression and the number of dedifferentiated Schwann cells., Conclusions: Resveratrol may promote axonal regeneration following replantation surgery for the treatment of nerve root avulsion injury; however, further studies are required to verify these findings in humans.

Chemokines-mediated neuroinflammation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. Chemokine CXCL9, CXCL10, and CXCL11 have been identified as a same subfamily chemokine which bind to CXC chemokine receptor 3 to exert functions. Our recent work found that CXCL10 is upregulated in spinal astrocytes after spinal nerve ligation (SNL) and acts on chemokine receptor CXCR3 on neurons to contribute to central sensitization and neuropathic pain, but less is known about CXCL9 and CXCL11 in the maintenance of neuropathic pain. Here, we report that CXCL9 and CXCL11, same as CXCL10, were increased in spinal astrocytes after SNL. Surprisingly, inhibition of CXCL9 or CXCL11 by spinal injection of shRNA lentivirus did not attenuate SNL-induced neuropathic pain. In addition, intrathecal injection of CXCL9 and CXCL11 did not produce hyperalgesia or allodynia behaviors, and neither of them induced ERK activation, a marker of central sensitization. Whole-cell patch clamp recording on spinal neurons showed that CXCL9 and CXCL11 enhanced both excitatory synaptic transmission and inhibitory synaptic transmission, whereas CXCL10 only produced an increase in excitatory synaptic transmission. These results suggest that, although the expression of CXCL9 and CXCL11 are increased after SNL, they may not contribute to the maintenance of neuropathic pain.

Transcription factors are proteins that modulate the transcriptional rate of target genes in the nucleus in response to extracellular or cytoplasmic signals. Activating transcription factors 2 (ATF2) and 3 (ATF3) respond to environmental signals and maintain cellular homeostasis. There is evidence that inflammation and nerve injury modulate ATF2 and ATF3 expression. However, the function of these transcription factors in pain is unknown. The purpose of this study was to investigate the contribution of ATF2 and ATF3 to nerve injury-induced neuropathic pain. L5/6 spinal nerve ligation induced tactile allodynia and thermal hyperalgesia. Moreover, nerve damage enhanced ATF2 and ATF3 protein expression in injured L5/6 dorsal root ganglia and spinal cord but not in uninjured L4 dorsal root ganglia. Nerve damage also enhanced ATF2 immunoreactivity in dorsal root ganglia and spinal cord 7 to 21 days post-injury. Repeated intrathecal post-treatment with a small-interfering RNA targeted against ATF2 (ATF2 siRNA) or anti-ATF2 antibody partially reversed tactile allodynia and thermal hyperalgesia. In contrast, ATF3 siRNA or anti-ATF3 antibody did not modify nociceptive behaviors. ATF2 immunoreactivity was found in dorsal root ganglia and spinal cord co-labeling with NeuN mainly in non-peptidergic (IB4 + ) but also in peptidergic (CGRP + ) neurons. ATF2 was found mainly in small- and medium-sized neurons. These results suggest that ATF2, but not ATF3, is found in strategic sites related to spinal nociceptive processing and participates in the maintenance of neuropathic pain in rats.

Objective: We investigated high resolution diffusion tensor imaging (DTI) of lumbar nerves with reduced field of view (rFOV) using 3 T MRI., Methods: DTI measured with rFOV was compared with conventional FOV (cFOV) 3.0 T MRI in 5 healthy volunteers and 10 patients with degenerative lumbar disorders. The intracanal, foramina and extraforamina of the L5 nerve were established as the regions of interest and fractional anisotropy (FA) values and apparent diffusion coefficient (ADC) values were measured. Image quality for tractography and FA maps and ADC maps, interindividual and intraindividual reliability of FA and ADC, and signal-to-noise (SNR) were studied., Results: Both of image qualities with tractography, FA map and ADC map showed that lumbar nerves were more clearly imaged with the rFOV. Intraindividual reliability was higher with rFOV compared with the conventional method for ADC values, while interindividual reliability was higher for both FA values and ADC values with the rFOV method over the conventional method (p < 0.05). Significantly higher SNR was obtained with rFOV compared with cFOV in the spinal canal (p < 0.05)., Conclusion: rFOV enabled clearer imaging of the lumbar nerve, allowing for more accurate measurement of FA and ADC values. Significantly higher SNR was obtained with rFOV compared with cFOV in the spinal canal. To our knowledge, this research showed for the first time the usefulness of rFOV in patients with degenerative lumbar disorders. High resolution DTI using rFOV may become useful in clinical applications because visualization of nerve entrapments and quantification of DTI parameters may allow more accurate diagnoses of lumbar nerve dysfunction. Advances in knowledge: Compared with traditional methods, rFOV allows for clear imaging of the lumbar nerve and enables accurate measurements of the FA and ADC values. High-resolution DTI with rFOV may be used to visualize nerve entrapments and allow for more accurate diagnosis of DTI parameter quantification with opportunities for clinical applications.

Pathological studies of early Guillain-Barré syndrome (GBS), defined as of 10days of disease onset, are scanty making it difficult to interpret the physiopathology of clinical and electrophysiological features. In 1949, Webb Haymaker and James Kernohan reported 50 clinico-pathological studies of fatal GBS cases, 32 of them having died between days 2 and 10 after onset. They established that the brunt of initial lesions, consisting of endoneurial oedema interpreted as degenerative, relied on spinal nerves. That this oedema was inflammatory was soon thereafter recognized. Two decades later, however, the pathogenic role of endoneurial oedema was disputed. In experimental allergic neuritis, considered an animal model of GBS, the initial lesion appearing on day 4 post-inoculation is marked inflammatory oedema in the sciatic nerve and lumbosacral nerve roots. Additional detailed clinico-pathological studies corroborated that the appearance of epi-perineurium at the subarachnoid angle, where anterior and posterior roots join to form the spinal nerve, is a pathological hotspot in early GBS, there developing inflammatory oedema, incipient demyelination and endoneurial ischemic zones with axonal degeneration. Furthermore, nerve ultrasonography has demonstrated predominant spinal nerve changes in early GBS, either demyelinating or axonal. Other outstanding Haymaker and Kernohan's contributions were to clarify the complex nosology of the syndrome bringing under the same rubric Landry's paralysis, acute febrile polyneuritis and GBS, and critically analyzing GBS exclusion criteria by then prevailing. It is concluded that the authors' legacy remains as relevant as ever., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Spinal synaptic plasticity is believed to drive central sensitization that underlies the persistent nature of neuropathic pain. Our recent data showed that synaptic plasticity in the dorsal horn is cell type specific: intense afferent stimulation produced long-term potentiation (LTP) in excitatory spinothalamic tract neurons (STTn), whereas it produced long-term depression (LTD) in inhibitory GABAergic interneurons (GABAn). In addition, reactive oxygen species (ROS) were shown to be involved in LTP in STTn (STTn-LTP) and in LTD in GABAn (GABAn-LTD). This study examined the roles of 2 biologically important ROS--superoxide [·O2] and hydroxyl radicals [·OH]--in neuropathic mechanical hyperalgesia and cell type-specific spinal synaptic plasticity. The [·O2] donor induced stronger mechanical hyperalgesia than the [·OH] donor in naive mice. The [·O2] scavenger showed greater antihyperalgesic effect than [·OH] scavengers in the spinal nerve ligation (SNL) mouse model of neuropathic pain. In addition, the [·O2] donor induced both STTn-LTP and GABAn-LTD, but the [·OH] donor induced only GABAn-LTD. On the other hand, the [·O2] scavenger inhibited STTn-LTP and GABAn-LTD induction in naive mice and alleviated SNL-induced potentiation in STTn and depression in GABAn. The [·OH] scavenger, however, inhibited depression in GABAn but did not interfere with potentiation in STTn. These results indicate that mechanical hyperalgesia in SNL mice is the result of the combination of STTn-LTP and GABAn-LTD. Behavioral outcomes compliment electrophysiological results which suggest that [·O2] mediates both STTn-LTP and GABAn-LTD, whereas [·OH] is involved primarily in GABAn-LTD.